Inflammasome inhibition in myocardial infarction reduces early reperfusion injury and suppresses systemic plaque activation.

BACKGROUND AND AIMS: Activation of innate immunity early after reperfused myocardial infarction (MI) contributes to reperfusion injury and acts systemically to accelerate atherosclerosis in remote non-culprit plaques. We hypothesized that inhibition of the NLRP3 inflammasome complex that is activated by damage-associated molecular patterns after MI would suppress these diverse maladaptive responses.

METHODS

In hyperlipidemic Ldlr-/-Apobec1-/- mice, MI was produced by LAD ischemia-reperufsion followed by randomization to no therapy or the NLRP3 inhibitor MCC950 started immediately upon reperfusion. Comprehensive echocardiography was performed at 1 h, 3 days, and 28 days. Echocardiographic molecular imaging for coronary microvascular platelet GPIbα, P-selectin, and VCAM-1 was performed at 1 h. Myocardial inflammation on day 3 was assessed by histology and flow cytometry, while infarct size and remote brachiocephalic artery plaque were assessed by histology on day 28.

RESULTS

Post-MI treatment with MCC950 suppressed all three molecular imaging markers of microvascular reperfusion injury which was associated with a significant reduction in post-MI myocardial inflammatory cell infiltrate on day 3. Treatment with MCC950 resulted in a greater degree of recovery over time in all echocardiographic measures of LV function, and reduced histologic infarct size by 50% (p < 0.01). Mice undergoing MI had accelerated brachiocephalic plaque growth versus non-ischemic age-matched controls which was inhibited by MCC950 resulting in smaller plaque size and necrotic cores, larger smooth muscle cap thickness, and evidence for fibrous cap endothelial-mesenchymal transformation.

CONCLUSIONS

In reperfused MI, pharmacologic inhibition of the NLRP3 inflammasome suppresses inflammatory and thromboinflammatory processes that contribute to early reperfusion injury, infarct expansion, and remote non-culprit plaque activation in later phases.